DESCRIPTION: (Applicant's abstract) This proposal is a competitive renewal of a grant concerned with the neurotransmitters that are involved in the sensitization of nociceptive dorsal horn neurons in several model pain states. The present application focuses on the neurotransmitters used in three different descending antinociceptive systems to inhibit transmission of signals by spinal cord nociceptive neurons, principally primate spinothalamic tract (STT) neurons. Two of these systems involve the lateral and the ventrolateral parts of the periaqueductal gray (PAG) and the other involves the anterior pretectal nucleus (APN). Hypothesis 1 is that the PAG is part of two antinociceptive systems driven by 1) noxious cutaneous stimuli and 2) by deep/visceral stimuli, whereas the APN is part of a third antinociceptive system activated by innocuous stimuli. However, both nuclei exert their inhibitory effects at the spinal cord level through release of some of the same neurotransmitters. Hypothesis 2 is that sensitization of STT cells involves second messenger systems that enhance the responses of glutamate receptors but desensitize inhibitory 5HT, NE and amino acid receptors and reduce the inhibition produced by PAG and APN, thus contributing to an increase in the responsiveness of STT cells. Hypothesis 3 is that there is an endogenous mechanism in the spinal cord for long-term analgesia that is activated by a second messenger cascade operating in opposition to central sensitization. This mechanisms resembles long-term depression in the brain. The overall goal of the project is to learn more about the endogenous analgesia systems so that improvements can be made in the treatment of pain.